Polycystic Kidney Diseases
Polycystic kidney diseases (PKD) are a group of disorders characterized by the presence of a large number of fluid-filled cysts throughout grossly enlarged kidneys (Gabow et al. (1993) Diseases of the Kidney, Schrier et al., eds.). In humans, PKDs can be inherited in autosomal dominant (ADPKD) or autosomal recessive (ARPKD) forms. ADPKD is the more common form and is the most common, dominantly-inherited kidney disease in humans, occurring at a frequency of about 1 in 800. ARPKD occurs at a frequency of about 1 in 10,000.
ADPKD is the most common single-gene disorder leading to kidney failure (see, Emmons et al. (1999) Nature 401:339-340). Since ADPKD is inherited as an autosomal dominant disorder, children of affected parents have a one in two chance of inheriting the disease. Although the kidney is the most severely affected organ, the disease is systemic and affects the liver, pancreas cardiovascular system and cerebro-vascular system. The major manifestation of the disorder is the progressive cystic dilation of renal tubules (Gabow (1990) Am. J. Kidney Dis. 16:403-413), leading to renal failure in half of affected individuals by age 50. Microdissection, histochemical and immunologic studies show that cysts in ARPKD kidneys arise from focal dilations of medullary collecting ducts (McDonald (1991) Semin. Nephrol. 11:632-642). Although end-stage renal failure usually supervenes in middle age (ADPKD is sometimes called adult polycystic kidney disease), children may occasionally have severe renal cystic disease.
ADPKD-associated renal cysts may enlarge to contain several liters of fluid and the kidneys usually enlarge progressively causing pain. Other abnormalities such as hematuria, renal and urinary infection, renal tumors, salt and water imbalance and hypertension frequently result from the renal defect. Cystic abnormalities in other organs, including the liver, pancreas, spleen and ovaries are commonly found in ADPKD. Massive liver enlargement can cause portal hypertension and hepatic failure. Cardiac valve abnormalities and an increased frequency of subarachnoid and other intracranial hemorrhage have also been observed in ADPKD. Progressive renal failure causes death in many ADPKD patients, and dialysis and transplantation are frequently required to maintain life in these patients.
Numerous biochemical abnormalities associated with this disease also are observed. These include defects in protein sorting, the distribution of cell membrane markers within renal epithelial cells, extracellular matrix, ion transport, epithelial cell turnover, and epithelial cell proliferation.
Three distinct loci have been shown to cause phenotypically indistinct forms of the ADPKD humans. These include polycystin-1 (PKD1) on chromosome 16, polycystin-2 (PKD2) on chromosome 4, and polycystin-3 (PKD3) (see, e.g., Reeders et al. (1985) Nature 317:542-544; Kimberling et al.. (1993) Genomics 18:467-472; Daoust et al. (1995) Genomics, 25:733-736). The ARPKD mutation is on human chromosome 6 (Zerres et al. (1994) Nature Genet. 7:429-432). Two proteins polycystin-1 (PKD1) and polycystin-2 (PKD2) are defective in human autosomal dominant polycystic kidney disease.
Mutations in either PKD1 or PKD2 cause almost indistinguishable clinical symptoms. Mutations in PKD1 or PKD2 account for 95% of autosomal dominant polycystic disease (Torres et al. 1998) Current Opinion in Nephrology and Hypertension 7:159-1691 with greater than 85-90% of disease incidence being due to mutations in PKD1.
The human PKD1 protein is an approximately 4,300 amino-acid integral-membrane glycoprotein with a large amino-terminal extracellular domain and a small, carboxy-terminal cytoplasmic tail. The human PKD1 gene (see, e.g., U.S. Pat. No. 5,891,628), including the complete nucleotide sequence of the gene's coding region (se SEQ ID No. 1) and encoded amino acid sequence, is known (see, SEQ ID No. 2). The predicted structure of the domains suggested that it is involved in cell-cell interactions or in interactions with the extracellular matrix. The PKD2 protein has similarities to PKD1, but its topology and domain structure suggest that it might act as a subunit of a cation channel. These proteins have been shown to interact directly (Mochizuki et at. (1996) Science 272:1339-1342, Qian (1997) Nature Generics 16:179-183).
Although these genes have been implicated in the disorders, their role in it etiology is not established. In addition, while studies of kidneys from ADPKD patients exhibit a number of different biochemical, structural and physiological abnormalities, the disorder's underlying causative biochemical defect is not known. Hence the molecular mechanisms leading to cyst enlargement and progressive loss of renal function in the PKDs are not understood. Presently there are no cures or effective treatments, other than palliative treatments, for these diseases. Hence there is a need to understand the underlying biochemistry and physiology of the ADPKD and to provide treatments.
Therefore, it is an object herein to provide a means to identify the underlying biochemistry and genetics of these diseases and to provide a means to identify compounds for use in treatment of these diseases.